Estrogens remain as potential compounds for fruitful drug development approaches as interventions for Alzheimer's Disease (AD). However, estrogen therapy has potential undesirable side-effects. We will evaluate para-quinols derived chemically from estrone (E1-quinol) and 17b-estradiol (E2-quinol), respectively in a murine AD model. These agents were proven to be novel brain-selective estrogen pro-drugs without problems associated with estradiol treatment. These agents (E1/E2-quinol versus the parent estrogens, E1 and E2, respectively) will be tested in in dtg AD and wild type mice. Data on biochemical, histological and behavioral responses will be collected to monitor the progression of the neurodegenerative disease, including behavioral testing, catecholamines, markers of AD neuropathology, and markers of brain inflammation in females. Our specific aims are the following: 1) Examine the behavioral consequences of treatment with E1/E2-quinol versus E1/E2 in dtg mice by conducting behavioral tests that assess the integrity of hippocampal-dependent and hippocampal- independent memory systems, and also attention and set-shifting. 2) Evaluate the effect of treatment with E1/E2-quinol versus E1/E2 on the progression of the AD neuropathology by treating control and wild type dtg mice at selected ages between 3 and 11 months of age with E1/E2-quinol versus E1/E2 and measuring: i) Morphological variables, including Ab proteins, plaques, activated microglia and astrocytes, in hippocampus, locus coeruleus (LC), basal forebrain, medial septum, and prefrontal cortex. ii) Biochemical markers, including Ab, catecholamines and their metabolites and markers of the cholinergic system. Broader Impact and Innovations: A major milestone in developing effective therapies for Alzheimer's disease is to show that a promising experimental agent ameliorates the loss of cognitive abilities and slows the progression of the AD neuropathology. We propose to test novel compounds that are classified according to their mechanism of action as prodrugs of endogenous estrogens in a murine model of AD. Female dtg mice backcrossed onto a C57Bl6 background will be used to assess for the first time the behavioral and neuropathological benefits of treatment with this novel, non-uterotrophic estrogen prodrug in comparison with those of the parent estrogen. If successful, these experiments will provide a framework for the pursuit of new therapeutic agents for the treatment of AD and brain inflammation. PUBLIC HEALTH RELEVANCE: Estrogens remain potential interventions for Alzheimer's Disease. We will evaluate para-quinols derived from estrone and 17b-estradiol as novel brain-selective estrogen pro-drugs in a mouse model of Alzheimer's Disease as interventions for neuropathology and cognitive impairment.